Elevated Interleukin-18 Receptor Accessory Protein Mediates Enhancement in Reactive Oxygen Species Production in Neutrophils of Systemic Lupus Erythematosus Patients.

Jie Ma,Ian Kar Yin Lam,Vera Sau Fong Chan,Chak-Sing Lau

doi:10.3390/cells10050964

Jie Ma, Ian Kar Yin Lam + Show 2 more

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https://doi.org/10.3390/cells10050964

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Journal: Cells	Publication Date: Apr 21, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: University of Hong Kong

Abstract

Interleukin-18 receptor accessory protein (IL18RAP) is an indispensable subunit for the IL-18 receptor (IL-18R) complex’s ability to mediate high-affinity IL-18 binding and signalling transduction. Interest in IL-18 in systemic lupus erythematosus (SLE) has been mostly focused on its role as a type 1 T helper cell-driving cytokine. The functional significance of IL18RAP in mediating the IL-18-driven response in myeloid cells in SLE remains largely unexplored. This study aimed to investigate the expression and function significance of IL18RAP in neutrophils of SLE patients. By qRT-PCR and Western blot analyses, elevated expressions of IL18RAP mRNA and protein were observed in neutrophils from SLE patients—particularly those with a history of nephritis. IL18RAP expression correlated negatively with complement 3 level and positively with disease activity, with higher expression in patients exhibiting renal and immunological manifestations. The increased IL18RAP expression in SLE neutrophils could be attributed to elevated type I interferon level in sera. Functionally, neutrophils from SLE patients showed higher IL-18-mediated enhancement in reactive oxygen species (ROS) generation, which showed positive correlation with IL18RAP expression and could be neutralized by anti-IL18RAP blocking antibodies. Taken together, our findings suggest that IL-18 could contribute to SLE pathogenesis through mediation of neutrophil dysfunction via the upregulation of IL18RAP expression.

Highlights

Systemic lupus erythematosus (SLE) is a female-biased, chronic systemic autoimmune disorder that affects multiple organ systems, including renal, nervous, musculoskeletal, haematological, respiratory, and cardiovascular systems [1,2]
We evaluated the expression of the IL-18Rα subunit in neutrophils and found no significant difference between healthy control (HC) and SLE patients (Figure S3)
Type I IFN has been shown to prime neutrophils to undergo NETosis, a cell death pathway with the formation of neutrophil extracellular traps (NETs), which release cellular proteins and DNA that further fuel the inflammatory process in SLE patients [40]. Our findings demonstrate another functional impact of type I IFN on neutrophil function in SLE, as highlighted by the heightened IL-18-mediated reactive oxygen species (ROS) production enhancement in neutrophils of SLE patients in relation to the elevated Interleukin-18 receptor accessory protein (IL18RAP) expression (Figure 4)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a female-biased, chronic systemic autoimmune disorder that affects multiple organ systems, including renal, nervous, musculoskeletal, haematological, respiratory, and cardiovascular systems [1,2]. Renal involvement is one of the most common clinical features of SLE, with approximately 50–60% of Asian SLE patients developing lupus nephritis (LN) during the disease course. It is a major cause of morbidity and mortality in SLE patients [3,4]. Imbalanced proinflammatory and anti-inflammatory cytokine production, together with abnormal responsiveness of immune cells to various cytokines, exacerbate immune dysregulation and contribute to tissue inflammation and organ damage in lupus [6]

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